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WO1997003986A1 - Composes fusionnes de triazole - Google Patents

Composes fusionnes de triazole Download PDF

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Publication number
WO1997003986A1
WO1997003986A1 PCT/JP1996/002004 JP9602004W WO9703986A1 WO 1997003986 A1 WO1997003986 A1 WO 1997003986A1 JP 9602004 W JP9602004 W JP 9602004W WO 9703986 A1 WO9703986 A1 WO 9703986A1
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WO
WIPO (PCT)
Prior art keywords
dihydro
ethyl
triazolo
piperidine
chlorophenyl
Prior art date
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PCT/JP1996/002004
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English (en)
Japanese (ja)
Inventor
Hiroshi Tanaka
Takanobu Kuroita
Seigo Ishibuchi
Hiroyuki Ushio
Takashi Futamura
Yoshitaka Ohashi
Kazuhiro Yano
Original Assignee
Yoshitomi Pharmaceutical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP8004034A external-priority patent/JPH09151186A/ja
Application filed by Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to AU64700/96A priority Critical patent/AU6470096A/en
Publication of WO1997003986A1 publication Critical patent/WO1997003986A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel condensed triazole compounds having affinity for dopamine D4 (hereinafter referred to as D4 ; the dopamine receptor subtypes described below also conform to this abbreviated method) receptor and their radioactive substances.
  • D4 receptor blockers are used in the medical field as central nervous system agents, especially antipsychotics.
  • dopamine receptors can be classified into two receptor subtypes according to their ligand-binding properties and their relationship to adenylate cyclase [Nature 2003]. Vol. 227, p. 93 (1979)].
  • One is the D, receptor type, which activates adenylate cyclase via a stimulatory G protein to produce cyclic AMP
  • the other is the D, receptor type, which suppresses adenylate cyclase via an inhibitory G protein, resulting in cytotoxicity.
  • Haloperidol a typical antipsychotic , shows higher affinity for D2 receptors than for D4 receptors. [Nature, Vol. 350, p. 610 (1991), Trends in Pharmacological Sciences]. col Sc i.) Vol. 15, p. 264 (1994)]. Moreover, it has also been reported that the effective therapeutic plasma concentration of clozapine correlates with the affinity constant for the D4 receptor [Trends in Pharmacological Sciences]
  • selective D 4 receptor antagonists can be expected as antipsychotic drugs that have few extracorporeal side effects and are effective against both positive and negative symptoms.
  • D4 receptor antagonists in order to elucidate the relationship between the D4 receptor and the pathogenesis of diseases such as schizophrenia, it is desired to develop a radioactive substance that targets the D4 receptor. is not known.
  • the present invention provides a compound that exhibits selective and strong blocking action against D4 receptors, is more effective against negative symptoms and positive symptoms than conventional compounds, and has fewer side effects, and D4 .
  • the object is to provide radioactive substances (radioligands) with selective affinity for receptors.
  • a novel condensed triazole compound represented by the following general formula (1), an optical isomer, or a pharmaceutically acceptable salt thereof has a higher D4 receptor than a D2 receptor. It was found that the compound (1) has a selective and strong blocking effect on the body, and furthermore, the compound (1) shows not only positive symptoms such as hallucinations and delusions that are characteristic in the acute phase, but also emotional numbness and apathy. While it is effective against negative symptoms such as autism, it also reduces side effects such as extrapyramidal symptoms and endocrine abnormalities seen when conventional antipsychotics with D2 receptor antagonists are administered. The present inventors have completed the present invention by finding that it can be a useful antipsychotic drug.
  • the present invention relates to the following condensed triazol compounds, pharmaceutical compositions containing them, and uses thereof.
  • R 1 and R 2 may be the same or different, and each is hydrogen, halogen, cyano, nitro, amino, acylamino, carbamoyl, alkylcarbamoyl, alkoxycarbonyl, acyl, alkylamino, aminoalkyl, alkylaminoalkyl, hydroxy, acyloxy , hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl;
  • W is methylene, a sulfur atom, SO, S02 , an oxygen atom or N— R3 (wherein R3 is hydrogen, alkyl, phenacyl, or optionally substituted arylalkyl or heteroarylalkyl ) and
  • X represents methylene, ethylene or vinylene
  • Y is absent or represents a linear or branched alkylene chain having 1 to 8 carbon atoms
  • Z is -NH2 , -NHR4 (wherein R4 is alkyl, cycloalkyl, optionally substituted arylalkyl, heteroarylalkyl or condensed heteroarylalkyl, or a substituent; represents aryl, heteroaryl or condensed heteroaryl which may be substituted), -N( R4 )( R5 ) (wherein R5 is alkyl, cycloalkyl, optionally substituted arylalkyl, heteroarylalkyl or condensed heteroarylalkyl, or optionally substituted aryl, heteroaryl or condensed heteroaryl, and R4 is as defined above. ), or cyclic amines of formula (a), (b) or (c)
  • cyclic amine -NN in formula (b) represents piperazine or homopiperazine, and the formula
  • the cyclic amine in (c) may have an additional oxygen atom in the ring.
  • A is absent or carbon represents a straight or branched alkylene chain having a number of 1 to 8
  • B is absent or represents a sulfur atom, an oxygen atom, carbonyl or hydroxymethyl
  • Re represents hydrogen, hydroxy, alkyl or alkoxy
  • R7 is hydrogen, optionally substituted aryl, heteroaryl or condensed heteroaryl, cycloalkyl, or optionally substituted arylalkyl, heteroarylalkyl or condensed heteroarylalkyl.
  • cyclic amine (a) is a cyclic amine represented by the following formula (2) (3), (4) (5) (6) or (7).
  • cyclic amine (b) is a cyclic amine represented by formula (8) or (9) below, an optical isomer thereof, or a pharmaceutically acceptable compound thereof. Soluble salt.
  • cyclic amine (c) is a cyclic amine represented by the following formula (10), (11) or (12); an optical isomer thereof or a pharmaceutically acceptable salt thereofc
  • R 1 represents hydrogen, halogen, nitro, amino, acyl, alkylamino, alkyl or alkoxy;
  • R 2 represents hydrogen, halogen or alkoxy
  • W represents methylene, sulfur atom or oxygen atom
  • X represents methylene, ethylene or vinylene
  • Y is absent or represents a linear alkylene chain having 1 to 3 carbon chains
  • Z represents a cyclic amine represented by formula (a), (b) or (c); the condensed triabole compound according to (1), which is a condensed triazol compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 each represent hydrogen
  • W represents a methylene, sulfur or oxygen atom
  • X represents methylene, ethylene or vinylene
  • Y is absent or represents a linear alkylene chain with 1 to 3 carbon chains
  • Z is expressed by formula (2' ) or formula (8' ) PT/JP96/02004
  • A' is absent or represents a linear alkylene chain having 1 to 4 carbon atoms
  • B' is absent or represents carbonyl
  • R6 ' represents hydrogen
  • R7 ' represents optionally substituted aryl or heteroaryl.
  • a pharmaceutical composition comprising the condensed triazole compound described in (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a radioactive condensed triazole compound represented by general formula ( ⁇ ) and uses thereof.
  • R 1 ' and R 2 ' may be the same or different and are each hydrogen, halogen, cyano, nitro, amino, acylamino, carbamoyl, alkyl carbamoyl, alkoxycarbonyl, acyl, alkylamino, aminoalkyl, alkylaminoalkyl, hydroxy, acyloxy, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, alkyl, alkenyl, alkynyl or alkoxy,
  • W is methylene, oxygen atom or N—R 3 (wherein R 3 is hydrogen, alkyl, Nasyl, or optionally substituted arylalkyl or heteroarylalkyl. ) and
  • T indicates tritium
  • Y is absent or represents a linear or branched alkylene chain having 1 to 8 carbon atoms
  • Z is —NH 2 , —NHR 4 (wherein R 4 is alkyl, cycloalkyl, optionally substituted arylalkyl, heteroarylalkyl or condensed heteroarylalkyl, or substituted may be aryl, heteroaryl or condensed heteroaryl), -N( R4 )( R5 ) (wherein R5 is alkyl, cycloalkyl, or may have a substituent; arylalkyl, heteroarylalkyl or condensed heteroarylalkyl, or optionally substituted aryl, heteroaryl or condensed heteroaryl as defined above), or formula (a), (b) or formula (c) cyclic amine
  • cyclic amine -NN in formula (b) represents piperazine or homopiperazine, represented by formula (c)
  • the cyclic amine in may further have an oxygen atom in the ring, Orolysine, piperidine, 3,6-dihydro-2 ⁇ -pyridine or morpholine, solid and dotted lines indicate single or double bonds, and ⁇ is absent or has 1 carbon represents a straight or branched alkylene chain having 8 from , B is absent or represents a sulfur atom, an oxygen atom, carbonyl or hydroxy methyl, R 6 represents hydrogen, hydroxy, alkyl or alkoxy, R7 is hydrogen, optionally substituted aryl, heteroaryl or condensed heteroaryl, cycloalkyl, or optionally substituted arylalkyl, heteroarylalkyl or condensed heteroarylalkyl; show.
  • halogen in R1 , R2 , R1 ' and R2 ' means chlorine, bromine, fluorine and iodine.
  • Acylamino means acetylamino, benzoylamino, cyclohexylcarbonylamino, cyclob- ⁇ -pyrcarbonylamino and the like, and the acyl moiety includes alroyl having 2 to 5 carbon atoms, benzoyl, naphthoyl and the like, and 3 to 3 carbon atoms. Cyclohexylcarbonyl of 6 is preferred.
  • Alkylcarbamoyl means methylcarbamoyl, cetylcarbamoyl, propylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl
  • Alkoxycarbonyl means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl and the like, and the alkoxy moiety preferably has 1 to 4 carbon atoms.
  • Acyl means formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, octanoyl, etc., and includes alkanoyl having 1 to 8 carbon atoms, benzoyl, naphthoyl, and other valroyl, and nicotinoyl, thenoyl, furoyl, and other heteroaryl compounds.
  • Luponyl is preferred.
  • Alkylamino means methylamino, dimethylamino, cechilamino, diethylamino, propylamino, dipropylamino, etc.
  • the alkyl moiety preferably has 1 to 4 carbon atoms, and the amino group is substituted with 1 to 2 alkyl groups.
  • Aminoalkyl means aminomethyl, 2-aminoethyl, 3-aminobutyryl, 4-aminobutyl and the like, and the alkyl moiety preferably has 1 to 4 carbon atoms.
  • Alkylaminoalkyl means methylaminomethyl, dimethylaminomethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl and the like, and the alkyl moiety preferably has 1 to 4 carbon atoms.
  • Acyloxy means acetyloxy, propionyloxy, butyryloxy, benzoyloxy and the like, and the acyl moiety is preferably an alkanoyl having 2 to 5 carbon atoms.
  • Hydroxyalkyl means hydroxymethyl, 1- or 2-hydroxyethyl, 1-, 2- or 3-hydroxypropyl and the like, and the alkyl portion preferably has 1 to 4 carbon atoms.
  • Acyloxyalkyl means acetoxymethyl, 2-acetoxyhetyl, 3-acetoxybutyryl, propionyloxymethyl and the like, and the acyl moiety is preferably alkanoyl having 2 to 5 carbon atoms.
  • Alkoxyalkyl means methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, 2-methoxychetyl, 2-ethoxychetyl, 3-methoxypropyl, etc., and alkoxy having 1 to 4 carbon atoms is Substituted alkyl of 1 to 4 carbon atoms is preferred.
  • Alkyl means methyl, ethyl, propyl, isopropyl, butyl, isopropyl, tertiary It represents butyl, pentyl, hexyl, heptyl, octyl, decyl, hexadecyl, octadecyl, etc., and ryukyl having 1 to 4 carbon atoms is preferred.
  • Alkenyl means vinyl, 1-propenyl, isopropenyl, etc., and preferably has 2 to 3 carbon atoms.
  • Alkynyl means echul and the like, and preferably has 2 to 3 carbon atoms.
  • Alkoxy means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxyne, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like, preferably alkoxy having 1 to 4 carbon atoms.
  • Alkylthio in R 1 and R 2 means methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like, and the alkyl moiety preferably has 1 to 4 carbon atoms.
  • Alkylsulfinyl means methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl and the like, and the alkyl moiety preferably has 1 to 4 carbon atoms.
  • Alkylsulfonyl means methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like, and the alkyl moiety preferably has 1 to 4 carbon atoms.
  • alkyl for R 3 examples include those similar to alkyl for R 1 , R 2 , R 1 ' and R 2 '.
  • Phalylalkyl means benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylmethyl, 3-naphthylpropyl, 4-naphthylbutyl, diphenylmethyl, etc.
  • the moiety is preferably phenyl or naphthyl, and the alkyl moiety preferably has 1 to 4 carbon atoms.
  • Heteroarylalkyl means pyridylmethyl, pyridylethyl, furylmethyl, furylmethyl, furilethyl, thienylmethyl, thienylethyl, etc.
  • Heteroaryl is preferably pyridyl, furyl, or thenyl, and the alkyl moiety preferably has 1 to 4 carbon atoms.
  • Substituents for arylalkyl and heteroarylalkyl include halogen such as fluorine, chlorine, bromine and iodine; haloalkyl such as trifluoromethyl; Alkyl such as butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy Alkoxy such as di, pentyloxy, hexyloxy, heptyloxy, and octyloxy are exemplified.
  • halogen such as fluorine, chlorine, bromine and iodine
  • haloalkyl such as trifluoromethyl
  • Alkyl such as butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy Alkoxy such as di, pentyloxy, hexyloxy, heptyloxy, and octyloxy are
  • Linear or branched alkylene chains having 1 to 8 carbon atoms in Y are methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, methylmethylene, dimethylmethylene.
  • 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, ethylmethylene, diethylmethylene, 1-ethylethylene, 2-ethylethylene, 1-methyltrimethylene, 2-methyltrimethylene Methylene, 3-methyltrimethylene and the like can be mentioned, with methylene or ethylene being preferred.
  • Alkyl for R 4 and R 5 means methyl, ethyl, propyl, isopropyl, butyl, isoptyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, decyl, hexadecyl, octadecyl, etc. Preferred carbon atoms are The number is 1-4. Cycloalkyl means cyclopropyl, cyclopentyl, cyclohexyl and the like, and preferably has 3 to 6 carbon atoms.
  • Farylalkyl means benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-naphthylpentyl, 4-naphthylbutyl, diphenylmethyl, etc.
  • the aryl moiety is preferably phenyl or naphthyl, and the alkyl moiety preferably has 1 to 4 carbon atoms.
  • Heteroarylalkyl means pyridylmethyl, 2-pyridylethyl, furylmethyl, 2-furylethyl, thienylmethyl, 2-thienylethyl, etc.
  • Heteroaryl means pyridyl, furyl, and thenyl, and the alkyl moiety has 1 to 4 carbon atoms. is preferred.
  • Paryl means phenyl, naphthyl, 2-indanyl and the like, with phenyl being preferred.
  • Heteroaryl means pyridyl, furyl, thienyl, pyrimidyl and the like, preferably pyridyl and pyrimidinyl.
  • Fused heteroaryl includes 1,4-benzodioxane-2-yl, 6-acetyl-3-ethyl-4,5,6,7-tetrahydrocheno[2,3-c]pyridine-2-yl, 1 , 2-benzoisothiazol-3-yl, 1, 2-benzoisothiazol-3-yl, indole benzo[b]furan-3-yl, benzo[b]thiophen-3-yl and the like, with 1,2-benzoisoxazol-3-yl being preferred.
  • Condensed heteroarylalkyl means indol-3-ylmethyl, 2-(indol-3-yl)ethyl, 3-(indol-3-yl)propyl, benzo[b]furan-3-ylmethyl, 2-(benzo [b]furan-3-yl)ethyl, benzo[b]thiophene-3-ylmethyl, 2-(benzo[b]thiophene-3-yl)ethyl, etc., and benzo[b]furan-3 -ylmethyl, benzo[b]thiophene-3-ylmethyl are preferred.
  • substituents include halogens of fluorine, chlorine, bromine and iodine, haloalkyl such as trifluoromethyl, alkyl such as methyl, ethyl, propyl, isopropyl, ptyl, isobutyl and tertiary butyl, methoxy, ethoxy, Alkoxy such as propoxy, isopropoxy, butoquine, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy, hydroxy, nitro, amino, methylamino and dimethylamino.
  • haloalkyl such as trifluoromethyl
  • alkyl such as methyl, ethyl, propyl, isopropyl, ptyl, isobutyl and tertiary butyl, methoxy, ethoxy
  • Alkoxy such as propoxy, isoprop
  • Cyclic amines of formula (a) in Z include the following.
  • Examples of ring-fused amines of formula (b) include: ⁇ N , day,
  • Cyclic amines of formula (c) include ⁇
  • the linear or branched alkylene chain having 1 to 8 carbon atoms in A includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, methylmethylene, dimethylmethylene, 1-methylethylene, 2-methylethylene, 1, 1-dimethylethylene, 2,
  • 3-methyltrimethylene and the like can be mentioned, with methylene or ethylene being preferred.
  • Alkyl for R6 includes methyl, ethyl, propyl, isopropyl, butyl, isoptyl, tertiary butyl and the like, preferably alkyl having 1 to 4 carbon atoms.
  • Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy and the like, with alkoxy having 1 to 4 carbon atoms being preferred.
  • aryl optionally substituted aryl, heteroaryl or condensed heteroaryl , cycloalkyl, optionally substituted arylalkyl, heteroaryl
  • roarylalkyl or condensed heteroarylalkyl include the same as those for R 4 and R 5 .
  • substituents include fluorine, chlorine, bromine, iodine halogen, haloalkyl such as trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isopropyl, tertiary Alkyl such as butyl, alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoquine, isobutoxy, tertiary butoxy, pentyloquine, hexyloxy, heptyloxy, and octyloxy, hydroquine, nitro, amino, methylamino, dimethylamino, alkylsulfonyl (methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.),
  • R, and R b are the same or different and represent hydrogen or alkyl such as methyl, ethyl, propyl, butyl, isopropyl and isobutyl)' etc. is mentioned.
  • the ring E is a benzene ring
  • a thiophene ring represented by is preferred, and the former is particularly preferred as the thiophene ring.
  • R1 and R1 ' are hydrogen, halogen, nitro, amino, acyl (acetyl, propionyl, etc.), alkylamino (methylamino, ethylamino, etc.), alkyl (methyl , ethyl, propyl, isopropyl, butyl, etc.) or alkoxy (methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.) are preferred, and R2 is hydrogen, halogen or alkoxy (methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.). ) is preferred.
  • both R 1 and R 2 , R 1 ′ and R 2 ′ are hydrogen.
  • W is preferably methylene, a sulfur atom or an oxygen atom, particularly preferably an oxygen atom.
  • Y-Z Y is preferably absent or a linear alkylene chain having 1 to 4 carbon atoms, and Z is preferably a cyclic amine represented by formula (a), (b) or (c). Better stomach. Further, among the cyclic amines of formula (a), formula (2'), among the cyclic amines of formula (b), formula (8'), and among the cyclic amines of formula (c), formula (10')
  • aryl for R7 ' includes phenyl, naphthyl, or phenyl having 1 to 2 substituents such as halogen, methyl, trifluoromethyl, methoxy, nitro, amino and methylamino, and heteroaryl Examples include chenyl and the like.
  • Condensed heteroaryls include 1,2-benzoisoxazol-3-yl, benzo[b]furan-3-yl, having up to 3 substituents such as halogen, methyl, trifluoromethyl, methoxy, etc. 1,4-benzodioxane-2-yl, 6-acetyl-2-ethyl-4,5,6,7-tetrahydrocheno[2,3-c]pyridin-3-yl and the like.
  • the general formula (1) includes the following three modes of compound according to the definition of X.
  • Preferred compounds of general formula (1) are 3-(1-(2-(4-chlorophenyl)ethyl)piperidine-4-yl)-6,7-dihydro-5H-1,2,4-triazolo [3,4-a] [2] Benzazepines,
  • Pharmaceutically acceptable salts of compounds of general formula (1) include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) or organic acids (acetic acid, propionic acid, succinic acid, glycolic acid). , lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, ascorbic acid, etc.).
  • the compounds of general formula (1) and their pharmaceutically acceptable salts may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the present invention. be.
  • the compound of general formula (1) has an asymmetric atom, it has at least two optical isomers. These optical isomers and their racemates are included in the present invention.
  • the compound of general formula (1) and the compound of the present invention included in general formula (1) can be synthesized by the following methods (1) to (18).
  • a compound of general formula (1) is obtained by reacting at room temperature to 200°C for 1 to 24 hours in the presence of a compound represented by:
  • a compound of general formula (13) is treated with a thionating agent such as phosphorus pentasulfide, Lawesson's reagent [2,4-bis(4 -methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide] and the like, at room temperature or at the reflux temperature of the solvent general formula (16)
  • a thionating agent such as phosphorus pentasulfide, Lawesson's reagent [2,4-bis(4 -methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide] and the like
  • a compound represented by is obtained.
  • This compound is represented by the general formula ( A compound of general formula (1) is obtained by reacting at room temperature to 200 eC for 1 to 24 hours in the presence of the compound represented by 15).
  • the compound of general formula (16) is treated with benzyl chloride, p-nitrobenzyl chloride, methyl iodide in a suitable solvent that does not inhibit the reaction (tetrahydrofuran, diethyl ether, dioxane, water or a mixed solvent thereof, etc.) etc., in the presence of a base such as potassium hydroxide or lithium tertiary butoxide at room temperature or the reflux temperature of the solvent for ⁇ ⁇ 24 hours to give the general formula (17)
  • R8 represents methyl, benzyl, ⁇ -nitrobenzyl, etc., and other symbols are as defined above.
  • a compound represented by is obtained. This compound is dissolved in a suitable solvent (methanol, ethanol, butanol, ethylene glycol, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, or any mixed solvent thereof).
  • the compound of general formula (1) is obtained by reacting it with the compound of formula (15) at room temperature or at the reflux temperature of the solvent for 1 to 24 hours.
  • G1 represents chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., and R4 has the same definition as above);
  • a base such as triethylamine, pyridine, dimethylaminopyridine, or the like, under ice-cooling or at room temperature for 1 to 24 hours, a reaction of the general formula (20) 0 ⁇
  • G2 represents chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.
  • R5 has the same definition as above.
  • G 3 is chlorine, bromine, iodine, methanesulfonyloxy, p-toluene Rulfonyloxy, trifluoromethanesulfonyloxy and the like are shown, and other symbols are as defined above.
  • a compound represented by the general formula (26) in the presence of a base such as potassium carbonate, sodium hydroxide, triethylamine, pyridine or dimethylaminopyridine under ice cooling or at room temperature for 1 to 24 hours.
  • a base such as potassium carbonate, sodium hydroxide, triethylamine, pyridine or dimethylaminopyridine
  • R 11 represents optionally substituted aryl or heteroaryl
  • m indicates a number from 1 to 7.
  • a tertiary amine such as triethylamine, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminobutopyl)carbodiimide, cyanophosphonic acid
  • a compound represented by is obtained.
  • a reactive derivative (acid chloride, acylimidazole, etc.) of the compound of general formula (28)
  • the reaction is carried out in an appropriate solvent (tetrahydrofuran, dichloromethane, chloroform, benzene, etc.) that does not inhibit the reaction.
  • the reaction proceeds under ice-cooling or at room temperature for 1 to 24 hours in the presence of a tertiary amine such as triethylamine or pyridine in a solvent such as benzene or any mixed solvent thereof.
  • a suitable solvent tetrahydrofuran, diethyl ether, toluene or or any mixed solvent thereof
  • a reducing agent such as lithium aluminum hydride or borane
  • a reduction reaction is carried out at room temperature for 1 to 24 hours from -78 to obtain the general formula (31)
  • a compound represented by is obtained.
  • an appropriate solvent methylene chloride, chloroform, dichloroethane, etc.
  • a base such as triethylamine, p-toluenesulfonyl chloride or methanesulfoyl chloride
  • a suitable dehydrogenating agent such as potassium carbonate, pyridine, or triethylamine
  • a solvent that does not inhibit the reaction such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran, diethyl ether, or any mixed solvent thereof.
  • the starting compounds used in the above methods can be synthesized by the following method.
  • R 9 represents a protecting group that is not affected by the reaction, such as a tertiary butoxycarbonyl group or a benzyloxycarbonyl group. Other symbols are as defined above.
  • the compound of general formula (18) can be obtained by deprotecting the compound of general formula (42) according to a conventional method by reacting with a suitable acid such as hydrochloric acid, hydrobromic acid, trifluoroacetic acid, etc. .
  • a suitable acid such as hydrochloric acid, hydrobromic acid, trifluoroacetic acid, etc.
  • a compound of general formula (14), (16) or (17) is dissolved in an appropriate solvent (methanol, ethanol, butanol, ethylene glycol, N-methyl-2-pyrrolidone, 1, 3-dimethyl-2-imidazolidinone or any mixed solvent thereof), general formula (43) or (44)
  • R 9 represents a protective group that does not affect the reaction, such as a tertiary butoxycarbonyl group or a benzyloxycarbonyl group. Other symbols are as defined above.
  • the compound of general formula (23) or general formula (24) is prepared by treating the compound of general formula (45) or (46) with an appropriate acid such as hydrochloric acid, hydrobromic acid, It can be obtained by deprotecting with the action of refluoroacetic acid or the like.
  • R 10 represents a protective group that does not affect the reaction, such as a methoxymethyl group, a tetrahydrovilanyl group, and a triethylsilyl group. Other symbols are as defined above.
  • R'' and R2 ' are the same or different and are hydrogen, halogen, cyano, nitro, amino, azilamino, carbamoyl, alkyl carbamoyl, alkoxycarbonyl, acyl, alkylamino, aminoalkyl, alkylaminoalkyl , hydroxy, acyloxy, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, alkyl, alkenyl, alkynyl or alkoxy, W is methylene, an oxygen atom or N— R3 (wherein R3 is hydrogen, alkyl, phenacyl, or optionally substituted arylalkyl or heteroarylalkyl), and other symbols are as defined above. ]
  • a suitable solvent that does not inhibit the reaction methanol, ethanol, isopropyl alcohol, ethyl acetate, water, acetic acid, sodium hydroxide aqueous solution, or any mixed solvent thereof
  • a suitable reduction catalyst Platinum, palladium, nickel, rhodium, ruthenium, and catalysts adsorbed on carriers, etc.
  • G1 represents chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., and R4 is as defined above.
  • G2 represents chlorine, bromine, iodine, methanesulfonyloxy, ⁇ -toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.
  • R5 is as defined above.
  • a compound represented by the general formula (52) in the presence of a base such as triethylamine, pyridine, or dimethylaminopyridine under ice cooling or at room temperature for 1 to 24 hours.
  • a base such as triethylamine, pyridine, or dimethylaminopyridine
  • G3 represents chlorine, bromine, iodine, methanesulfonyloxy, ⁇ -toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., and other symbols are as defined above.
  • a compound represented by the general formula (55) in the presence of a base such as potassium carbonate, sodium hydroxide, triethylamine, pyridine or dimethylaminopyridine under ice cooling or at room temperature for 1 to 24 hours.
  • a base such as potassium carbonate, sodium hydroxide, triethylamine, pyridine or dimethylaminopyridine
  • a suitable solvent tetrahydrofuran, (dichloromethane, dimethylformamide, or any mixed solvent thereof), general formula (28)
  • R 11 represents optionally substituted aryl or heteroaryl, and m represents a number from 1 to 7.
  • reaction is carried out in an appropriate solvent (tetrahydrofuran, dichloromethane, chloroform, benzene, etc.) that does not inhibit the reaction. or any mixed solvent thereof) in the presence of a tertiary amine such as triethylamine or pyridine under ice cooling or at room temperature for 1 to 24 hours.
  • an appropriate solvent tetrahydrofuran, dichloromethane, chloroform, benzene, etc.
  • a compound represented by is obtained.
  • the compound of general formula (61) is treated with p-toluenesulfonyl chloride or methanesulfonyl chloride in the presence of a base such as triethylamine in a suitable solvent (methylene chloride, chloroform, dichloroethane, etc.) that does not inhibit the reaction.
  • a base such as triethylamine
  • a suitable solvent methylene chloride, chloroform, dichloroethane, etc.
  • a compound such as potassium carbonate, pyridine, triethylamine, etc.
  • Pharmaceutically acceptable salts of the compound of general formula (1) include acid addition salts with inorganic acids or organic acids. acid, sulfuric acid, phosphoric acid, nitric acid, etc.), organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-Toluenesulfonic acid, camphorsulfonic acid, ascorbic acid, etc.) can be treated to form a salt.
  • the compound of the present invention thus obtained can be isolated and purified by conventional methods such as recrystallization and column chromatography.
  • the resulting product when the resulting product is a racemate, it can be resolved into the desired optically active form, for example, by fractional recrystallization of a salt with an optically active acid, or by passing through a column filled with an optically active carrier. can be done. Individual diastereomers can be separated by means of fractional crystallization, chromatography and the like. These can also be obtained by using optically active starting compounds. Stereoisomers can also be isolated by recrystallization, column chromatography, and the like.
  • the compounds, optical isomers, or pharmaceutically acceptable salts thereof of the present invention are D4 receptor antagonists that have a selective and strong blocking action on D4 receptors, and thus can reduce not only positive symptoms but also negative symptoms. It is a useful antipsychotic drug that also shows effects on symptoms. In addition, it is expected as an antipsychotic drug that alleviates the side effects such as extraphysical symptoms and endocrine abnormalities seen when conventional antipsychotic drugs with D2 receptor antagonism are administered. In addition, since the compounds of general formula (1) have high affinity and selectivity for D4 receptors, radioactive substances (radioligands) of these compounds are industrially used as selective radioligands for D4 receptors. It is a highly useful compound.
  • the radioligands of the general formula ( ⁇ ) are prepared from membrane fractions (cerebral cortex, hippocampus, striatum, etc.) of human or animals (mouse, rat, guinea pig, dog, monkey, etc.). D4 receptor binding using D4 receptor-expressing cells cloned from humans and other animals or membrane fractions prepared from various parts of the body. The test method can be used to screen for compounds that have affinity for the D4 receptor.
  • autoradiography labeled with D4 receptors enables us to know the distribution and number of D4 receptors in humans or animals, or changes in the number of D4 receptors in the brains of schizophrenic patients.
  • the compound of the present invention is combined with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agents, emulsifiers, diluents, solubilizers, etc.) and pharmaceutical compositions or preparations (tablets, pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions) , solutions, injections, drops, suppositories, etc.) can be administered orally or parenterally.
  • a pharmaceutically acceptable carrier excipient, binder, disintegrant, flavoring agent, flavoring agents, emulsifiers, diluents, solubilizers, etc.
  • pharmaceutical compositions or preparations tablettes, pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions
  • solutions injections, drops, suppositories, etc.
  • Pharmaceutical compositions can be formulated according to conventional methods
  • parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion, and the like.
  • injectable preparations such as sterile injectable aqueous or oleaginous suspensions, can be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. can.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally administrable diluent or solvent such as an aqueous solution.
  • Vehicles or solvents that can be used include water, Ringer's solution, isotonic sodium chloride solution, and the like.
  • sterile non-volatile oils can also be used as a normal solvent or suspending medium.
  • any non-volatile oil or anti-fat can be used.
  • natural or synthetic or semi-synthetic fatty oils or fatty acids can be used, and natural or synthetic or semi-synthetic mono-, di- or triglycerides.
  • Suppositories for rectal administration consist of the drug and suitable non-irritating excipients, such as cocoa butter and polyethylene glycols, which are solid at normal temperature but liquid at the temperature of the intestinal tract. It can be produced by mixing with something that melts and releases the drug.
  • Solid dosage forms for oral administration include those described above, such as powders, granules, tablets, pills, and capsules.
  • the active ingredient compound is combined with at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, It can be mixed with pectins, tragacanth gums, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides.
  • Such dosage forms can also contain further additives as usual, for example inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbins, etc., ascorbine.
  • Antioxidants such as acids, monotocofurol and cysteine, disintegrants, binders, thickeners, buffers, sweetening agents, flavoring agents, perfumes and the like. Tablets and pills can also be manufactured with an enteric coating.
  • Liquid formulations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which contain inert diluents commonly used in the art, such as water. You can stay.
  • Dosage may vary depending on age, body weight, general health, sex, diet, time of administration, method of administration, rate of excretion, combination of drugs, degree of medical condition being treated in the patient at the time, or other factors. It can be determined in consideration of factors.
  • the compound of the present invention, its optical isomer or its pharmaceutically acceptable salt can be used safely with low toxicity, and its daily dose depends on the condition and body weight of the patient, the type of compound, and the route of administration. For example, parenterally subcutaneously, intravenously, intramuscularly or intrarectally, about 0.
  • AZB preferably 0.01-20 mg Z people administered on Z days, or orally about 0.01 to 15 mg/day, preferably 0.1 to 100 mg
  • FIG. 1 shows part of the DNA sequences of D4.2 and D4.5.
  • FIG. 2 shows part of the base sequences of DNAs of D4.2 and D4.5, which follows FIG.
  • FIG. 3 shows part of the base sequences of DNAs of D4.2 and D4.5, which follows FIG.
  • FIG. 4 shows part of the base sequences of DNAs of D4.2 and D4.5, which follows FIG.
  • FIG. 5 shows part of the DNA base sequences of D4.2 and D4.5, and shows the part following FIG.
  • FIG. 6 shows part of the base sequences of DNAs of D4.2 and D4.5, which follows FIG.
  • FIG. 7 shows part of the base sequences of DNAs of D4.2 and D4.5, which follows FIG.
  • the present compound can also be obtained by reacting hetetralone with hydroxylamine and subjecting the resulting oxime compound to a Beckmann rearrangement reaction.
  • 2,3-dihydro-7,8-dimethoxy4H-1,4-4H-1,4- was obtained by carrying out the same reaction and treatment as in Synthesis Example 2 using 6,7-dimethoxychromanone, sodium azide and concentrated sulfuric acid. Benzoxazepine-5-one is obtained.
  • 2,3-dihydro-1-methyl-4H-1,4-benzodiazepine-5- was obtained by carrying out the same reaction and treatment as in Starting Material Synthesis Example 20 using aluminum chloride, methyl N-methylanthranilate and aziridine. On is obtained.
  • Raw Material Synthesis Example 22 0.97 g of the 2,3,4,5-tetrahydro-1H-2-benzozepine-1-one obtained in Raw Material Synthesis Example 1 and 1.33 g of the Lawess0n reagent were added to a 30 mL solution. The l toluene solution was heated to reflux for 3-4 hours. After completion of the reaction, the reaction solution was treated with an aqueous sodium hydrogencarbonate solution, the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from toluene to obtain 1.1 g of 2,3,4,5-tetrahydro-1H-2-benzazepine-1-thione.
  • Example 2 2,3-dihydro-7-methoxy-4H-1,4-benzothiazepine-5-thione is obtained by the same reaction and treatment as in 2.
  • Raw material synthesis example 4 9 After dissolving 3.8 g of 2,3-dihydro-4H-1,4-benzothiazepine-5-thione obtained in Starting Material Synthesis Example 28 in a mixed solvent consisting of 30 ml of water and 30 ml of tetrahydrofuran, , 2.1 g of potassium hydroxide and 3.4 g of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was treated with water, and the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • 5-Methylthio-1,4-benzothiazepine is obtained by carrying out the same reaction and treatment as in Starting Material Synthesis Example 22 using methyl iodide and lithium hydroxide.
  • lactam form obtained in the above raw material synthesis example as a starting material, it is well known in organic chemistry.
  • the lactam derivatives described in Starting Material Synthesis Examples 79-91 are obtained by chemically modifying the thiophene ring by chemical reactions such as halogenation, Mannich reaction, Friedel-Crafts reaction, and the like.
  • Example 1 Using the 2,3-dihydro-5-methylthio-1,4-benzothiazepine and 1-(tertiary-butoquincarbonyl)-piperidine-4-carbohydrazide obtained in Starting Material Synthesis Example 49, Example 1 and 3-(Piperidine-4-yl)-1,2,4-triazolo[4,3-d][1,4]benzothiazepine can be obtained by similar reaction and treatment.
  • Example 6 Using 1-benzyl-2,3-dihydro-5-methylthio-1,4-benzodiazepine and 1-(tertiary-butoxycarbonyl)piveridine-4-carbohydrazide obtained in 2, Example 1 7-Benzyl-3-(piperidine-4-yl)-1,2,4-triazo[4,3-d][1,4]benzodiazepine is obtained by the same reaction and treatment as in .
  • Example 1 2 2.4 g of 2,3-dihydro-5-methylthio-1,4-benzoxazepine obtained in Starting Material Synthesis Example 44 and 1-(2-(4-chlorophenyl)ethyl)piperidine-4-carbohydrate 3.8 g of hydrazide was added to 1,3-dimethyl-2-imidazolidinone 10 Om 1 and stirred at 280 for 2-3 hours. The reaction mixture was treated with water, and the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • reaction solution was treated with an aqueous sodium hydrogencarbonate solution, the organic layer was extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol-30:1) to give methanesulfonic acid'2-(5,6-dihydrogen 6.5 g of 1,2,4-triazolo[4,3-d][1,4]benzoxazepine-3-ethyl ester were obtained. Melting point 141-142. C.
  • Methanesulfonic acid obtained in Example 36 2-(5,6-dihydro-1,2 4-triazolo[4,3-d][1,4]benzoxazepin-3-yl)ethyl ester 0.7 g, 4-(3-trifluoromethylphenyl)piperazine.1 1.0 g of hydrochloride, 2 g of potassium carbonate and 1 g of potassium iodide were added to 20 ml of dimethylformamide and heated with stirring at 70° C. for 2 to 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the resulting residue.
  • Methanesulfonic acid 2-(5,6-dihydro-1,2,4-triazolo[4,3-d][1,4]benzoxazepin-3-yl) obtained in Example 36 0.7 g of ethyl ester, 0.5 g of 4-benzhydrylpiperazine and 1 g of potassium carbonate were added to 20 ml of dimethylformamide, and the mixture was heated and stirred at 70°C for 2 to 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the resulting residue. The organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate.
  • Methanesulfonic acid 2-(5,6-dihydro-1,2,4-triab[4,3-d][1,4]benzoxazepine-3-yl )-ethyl ester 0.7 g, 6-fluoro-3-(piperidine-4-yl)benzo[d]isoxazol-1 hydrochloride 0.5 g and potassium carbonate 1 g were dissolved in 20 ml of dimethylformamide. After completion of the reaction, the solvent was evaporated under reduced pressure, an aqueous solution of sodium carbonate was added to the resulting residue, and the organic layer was extracted with chloroform.
  • Methanesulfonic acid 2-(5,6-dihydro-1,2,4-triazolo[4,3-d][1,4]benzoxazepine-3-yl) obtained in Example 36 0.7 g of ethyl ester, 0.3 g of 4-phenylbiperazine and 1 g of potassium carbonate were added to 20 ml of dimethylformamide, and the mixture was heated and stirred at 70°C for 2 to 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the resulting residue. The organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and isopropyl ether was added to the resulting residue to crystallize it.
  • Methanesulfonic acid 2-(5,6-dihydro-1,2,4-triab[4,3-d][1,4]benzoxazepin-3-yl) obtained in Example 36 Add 0.7 g of ethyl ester, 0.4 g of 4-(2-methoxyphenyl)piperazine and 1 g of potassium carbonate to 20 ml of dimethylformamide and stir at 70°C for 2-3 hours. Time heating Stirred. After completion of the reaction, the solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the resulting residue. The organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate.
  • Methanesulfonic acid 2-(5,6-dihydro-1,2,4-triazolo[4,3-d][1,4]benzoxazepin-3-yl) obtained in Example 36 Dimethyl ester 0.7 g, 4-benzylpiperazine 0.5 g, potassium carbonate 1 g Add 20 ml of methylformamide and 70. The mixture was heated and stirred at C for 2-3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the resulting residue. The organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate.
  • Methanesulfonic acid obtained in Example 36 2-(5,6-dihydro-1,2,4-triazolo[4,3-d][1,4]benzoxazepin-3-yl ) 0.7 g of ethyl ester, 0.5 g of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 1 g of lium carbonate and 20 mL of dimethylformamide. 1, and heated and stirred at 70°C for 2 to 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the resulting residue. The organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate.
  • Methanesulfonic acid 2-(5,6-dihydro-1,2,4-triazolo[4,3-d][1,4]benzoxazepin-3-yl) obtained in Example 36 20 ml of a dimethylformamide solution containing 0.6 g of ethyl ester, 0.4 g of 4-(4-fluorophenyl)piperazine and 1.0 g of potassium carbonate. The mixture was heated and stirred at C for 2-3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the resulting residue. The organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate.
  • Methanesulfonic acid 2-(5,6-dihydro-1,2,4-triazolo[4,3-d][1,4]benzoxazepine-3-yl) obtained in Example 36 0.7 g of ethyl ester, 0.3 g of 4-phenylbiperidine and 1 g of potassium carbonate were added to 20 ml of dimethylformamide, and the mixture was heated and stirred at 70°C for 2 to 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the resulting residue. The organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate.
  • Methanesulfonic acid 2-(5,6-dihydro-1,2,4-triazolo[4,3-d][1,4]benzoxazepin-3-yl) obtained in Example 36 0.7 g of ethyl ester, 0.45 g of 4-(2,3-dichlorophenyl)piperazine, 1 g of sodium carbonate were added to 20 ml of dimethylformamide and stirred at 70°C. Heated and stirred for 2 to 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the resulting residue. The organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate.

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Abstract

Cette invention concerne des composés fusionnés de triazole correspondant à la formule générale (1) où chaque symbole est tel que défini dans la description. Cette invention concerne également des isomères optiques et des sels acceptables sur le plan pharmaceutique de ces composés, des compositions médicinales contenant ces composés, ainsi que des composés fusionnés de triazole radioactifs, leurs isomères optiques et leurs sels. Ces composés fusionnés de triazole, leurs isomères optiques et leurs sels acceptables sur le plan pharmaceutique, sont des antagonistes du récepteur D4 qui possèdent un effet sélectif et de blocage puissant sur ledit récepteur D4. Ils sont ainsi utiles en qualité d'agent antipsychotique efficace non seulement contre des syndromes positifs caractérisés par des hallucinations ou le délire, lesquels reflètent un état de schizophrénie aiguë, mais aussi contre les symptômes négatifs tel que l'apathie, l'autisme, etc. Ils peuvent également servir d'agent antipsychotique ayant des effets secondaires réduits, par exemple en ce qui concerne les symptômes extrapyramidaux et les anomalies endocriniennes qui accompagnent l'administration d'agents antipsychotiques traditionnels antagonistes du récepteur D2. Ces composés peuvent donc être utilisés comme médicaments contre des maladies telles que la schizophrénie. Les composés fusionnés de triazole radioactifs peuvent en outre être utilisés en qualité de radioligand possédant une affinité envers le récepteur D4 chez l'homme ou l'animal.
PCT/JP1996/002004 1995-07-19 1996-07-17 Composes fusionnes de triazole WO1997003986A1 (fr)

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WO2005082873A3 (fr) * 2004-02-27 2006-07-13 Bioagency Ag Nouveau compose 1,4-benzothiazepanes et leurs derives
WO2006023750A3 (fr) * 2004-08-23 2006-07-27 Merck & Co Inc Derives de triazole accoles inhibiteurs de la dipeptidyl peptidase-iv utilises dans le traitement ou la prevention du diabete
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US7393652B2 (en) 2000-05-10 2008-07-01 The Trustees Of Columbia University In The City Of New York Methods for identifying a chemical compound that directly enhances binding of FKBP12.6 to PKA-phosphorylated type 2 ryanodine receptor (RyR2)
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US8501777B2 (en) 2005-10-13 2013-08-06 Nsab, Filial Af Neurosearch Sweden Ab, Sverige 3,5-disubstituted phenyl-piperidines as modulators of dopamine neurotransmission
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USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
US11207308B2 (en) 2012-04-04 2021-12-28 Prilenia Neurotherapeutics Ltd. Pharmaceutical compositions for combination therapy

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USRE41315E1 (en) 1999-12-22 2010-05-04 Nsab, Filial Af Neurosearch Sweden Ab Modulators of dopamine neurotransmission
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
US7417043B2 (en) 1999-12-22 2008-08-26 Neurosearch Sweden Ab Modulators of dopamine neurotransmission
US7393652B2 (en) 2000-05-10 2008-07-01 The Trustees Of Columbia University In The City Of New York Methods for identifying a chemical compound that directly enhances binding of FKBP12.6 to PKA-phosphorylated type 2 ryanodine receptor (RyR2)
US7544678B2 (en) 2002-11-05 2009-06-09 The Trustees Of Columbia University In The City Of New York Anti-arrythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2)
US7312044B2 (en) 2003-03-07 2007-12-25 The Trustees Of Columbia University In The City Of New York Type 1 ryanodine receptor-based methods
US8710045B2 (en) 2004-01-22 2014-04-29 The Trustees Of Columbia University In The City Of New York Agents for preventing and treating disorders involving modulation of the ryanodine receptors
WO2005082873A3 (fr) * 2004-02-27 2006-07-13 Bioagency Ag Nouveau compose 1,4-benzothiazepanes et leurs derives
EP2127654A1 (fr) * 2004-03-25 2009-12-02 The Trustees of Columbia University in the City of New York Dérivés de la benzothiazepine comme inhbiteurs du récepteur de la ryanodine et de leur utilisation dans le traitement de maladies cardiaques
WO2005121088A1 (fr) * 2004-06-08 2005-12-22 A. Carlsson Research Ab Nouveaux phenylpiperidines disubstitue utilises comme modulateurs de la neurotransmission de la dopamine et de la serotonine
US20100256163A1 (en) * 2004-06-08 2010-10-07 Clas Sonesson Disubstituted phenylpiperdines/piperazines as modulators of dopamine neurotransmission
US8314126B2 (en) * 2004-06-08 2012-11-20 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpiperdines/piperazines as modulators of dopamine neurotransmission
US7625888B2 (en) 2004-08-23 2009-12-01 Merck & Co., Inc. Fused triazole derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
WO2006023750A3 (fr) * 2004-08-23 2006-07-27 Merck & Co Inc Derives de triazole accoles inhibiteurs de la dipeptidyl peptidase-iv utilises dans le traitement ou la prevention du diabete
US7884104B2 (en) 2004-10-01 2011-02-08 Merck Sharp & Dohme Corp. Aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
US8501777B2 (en) 2005-10-13 2013-08-06 Nsab, Filial Af Neurosearch Sweden Ab, Sverige 3,5-disubstituted phenyl-piperidines as modulators of dopamine neurotransmission
US9012476B2 (en) 2011-12-08 2015-04-21 IVAX International GmbH Hydrobromide salt of pridopidine
US9814706B2 (en) 2011-12-08 2017-11-14 Teva Pharmaceuticals International Gmbh Hydrobromide salt of pridopidine
US11207308B2 (en) 2012-04-04 2021-12-28 Prilenia Neurotherapeutics Ltd. Pharmaceutical compositions for combination therapy

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